The ERK (extracellular signal-regulated kinase) pathway is an evolutionarily conserved signal transduction module that controls cellular growth, differentiation and survival (Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage, Nat Rev Mol Cell Biol., 5, 875-85 (2004)). Activation of receptor tyrosine kinases (RTKs) by the binding of growth factors initiates GTP loading of RAS, which triggers the initial steps in the activation of the ERK pathway by modulating RAF family kinase function. Once activated, RAF participates in a sequential cascade of phosphorylation events that activate MEK, and in turn ERK. Unbridled signaling through the ERK pathway caused by activating mutations in RTKs, RAS or RAF, have been linked to a multitude of human cancers (Roberts, P. J. & Der, C. J., Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer, Oncogene, 26, 3291-310 (2007)). Of note, one member of the RAF family, B-RAF, is the most frequently mutated oncogene within the kinase superfamily (Greenman, C. et al., Patterns of somatic mutation in human cancer genomes, Nature, 446, 153-8 (2007)).
Not surprisingly, there has been a colossal effort to understand the underlying regulation of this family of kinases. Despite intense scrutiny, the mechanisms governing RAF activation remain only partially understood. In particular, the process by which its kinase domain becomes catalytically activated towards its substrate MEK remains elusive.
A greater understanding of the mechanisms that govern RAF activation would be useful as a means to identify novel therapeutic intervention strategies for disease such as cancer.